Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing.

Abstract	Neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Huntington's disease manifest with the neuronal accumulation of toxic proteins. Since autophagy upregulation enhances the clearance of such proteins and ameliorates their toxicities in animal models, we and others have sought to re-position/re-profile existing compounds used in humans to identify those that may induce autophagy in the brain. A key challenge with this approach is to assess if any hits identified can induce neuronal autophagy at concentrations that would be seen in humans taking the drug for its conventional indication. Here we report that felodipine, an L-type calcium channel blocker and anti-hypertensive drug, induces autophagy and clears diverse aggregate-prone, neurodegenerative disease-associated proteins. Felodipine can clear mutant α-synuclein in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug. This is associated with neuroprotection in mice, suggesting the promise of this compound for use in neurodegeneration.
Authors	Farah H Siddiqi, Fiona M Menzies, Ana Lopez, Eleanna Stamatakou, Cansu Karabiyik, Rodrigo Ureshino, Thomas Ricketts, Maria Jimenez-Sanchez, Miguel Angel Esteban, Liangxue Lai, Micky D Tortorella, Zhiwei Luo, Hao Liu, Emmanouil Metzakopian, Hugo J R Fernandes, Andrew Bassett, Eric Karran, Bruce L Miller, Angeleen Fleming, David C Rubinsztein
Journal	Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 1817 (04 18 2019) ISSN: 2041-1723 [Electronic] England
PMID	31000720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Neuroprotective Agents SNCA protein, human Snca protein, mouse alpha-Synuclein Felodipine
Topics	Animals Animals, Genetically Modified Autophagy (drug effects) Cell Line Cerebral Cortex (cytology, pathology) Disease Models, Animal Drug Repositioning Embryo, Mammalian Embryo, Nonmammalian Felodipine (pharmacology, therapeutic use) Female Humans Induced Pluripotent Stem Cells Male Mice Mice, Inbred C57BL Mutation Neurodegenerative Diseases (drug therapy, genetics, pathology) Neurons (drug effects, pathology) Neuroprotective Agents (pharmacology, therapeutic use) Primary Cell Culture Swine Swine, Miniature Treatment Outcome Zebrafish alpha-Synuclein (genetics, metabolism)

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